Canine melanoma is the umbrella term for a group of melanocytic tumor subtypes that are so complex and diverse (yet distinct from each other) that they can sometimes seem as if they are different diseases entirely. What all types of melanomas do have in common is that they form when normal melanocytes (cells that are responsible for producing melanin) divide and grow out of control.
Melanomas are classified as either benign or malignant tumors. Fortunately, the majority of melanomas that occur in dogs are benign; this form of melanoma is typically referred to as a melanocytoma. These tumors are not cancerous and usually do not become cancerous, nor do they interfere with the function of normal cells. They will often cease growing once they reach a certain size and they do not invade other tissues. Furthermore, they do not metastasize, and they tend to not grow back when surgically removed.
In contrast, malignant melanomas, accounting for 5 to 7% of all canine melanomas, are highly aggressive and can metastasize to vital organs very quickly. About 100,000 cases of malignant melanoma in dogs are diagnosed in the U.S. each year.
This cancerous tumor tends to form in areas of the body that are pigmented, and while the tumors are usually brown or black, they can appear pink, tan, or even white, depending on the level of melanin being produced. These are most commonly seen in middle-aged to older dogs (average age of 9 years) with no gender predilection.
The location in the body will determine the specific biological behavior of this cancer. Dogs are often asymptomatic until the cancer has spread.
The etiology of canine melanoma is not known, but researchers believe that it may due to a combination of environmental factors and genetics. It is also suspected that chemical agents, stress, trauma, or excessive licking of a particular spot could be factors; if cells are triggered to randomly multiply, it can increase the chance of mutation during cell division and result in the formation of malignant cells.
While ultraviolet light exposure is a major cause of melanoma in humans, it is not usually associated with the canine form due to their protective coat of fur.
Malignant melanoma in dogs is thought to reflect a strong genetic component with the following breeds being over-represented: Airedales, Bloodhounds, Boston Terriers, Chihuahuas, Chow Chow, Cocker Spaniels, Dachshunds, Doberman Pinschers, English Springer Spaniels, Golden Retrievers, Gordon Setters, Irish Setters, Pekingese, Poodles, Rottweilers, Miniature and Giant Schnauzers, Springer Spaniels, Scottish Terriers, and Tibetan Spaniels.
The disease is also more likely to appear in the toes or toenail bed of black dogs; small breeds with heavily pigmented mucous membranes in the mouth are reported to be at an increased risk of oral melanoma.
Diagnosis of canine malignant melanoma is typically obtained through cytology from a fine-needle aspirate of the tumor and/or biopsy and histopathology, but they are also known for being challenging to diagnose.
When melanomas are pigmented, the pathologist can usually see the melanin granules and characteristic cell morphology in the sample. Difficulties arise when melanocytic tumors lack pigmentation and the cell morphology varies tremendously.
The histopathological results of the biopsy may resemble carcinoma, sarcoma, lymphoma, or an osteogenic tumor. At this point, additional testing with special stains for immunohistochemical (IHC) markers (Melan-A, PNL-2, tyrosine reactive protein TRP-1 and TRP-2) is required; this screening is highly sensitive and specific for detecting melanocytes. It is vital to have an accurate diagnosis as that will determine the treatment protocol used and the prognosis.
Further diagnostic tests to assess the dog’s overall health and determine the stage of the disease may include a complete blood count; serum biochemical profile; urinalysis; chest radiographs and abdominal ultrasound to look for evidence of metastasis; and lymph node aspirate to check if cells have spread to the lymphatic system.
In dogs with the oral form of melanoma, especially if the lymph nodes are noted to be enlarged, further testing is warranted to check for metastasis in the abdominal lymph nodes, liver, adrenal glands, and other sites.
For oral tumors, radiographs and/or a computed tomography (CT) scan may be recommended.
Because digital (toe) melanoma often involves bone destruction, radiographs should be taken of the affected foot.
Specific diagnostic techniques for ocular melanoma involve slit-lamp examination, tonometry (intraocular pressure), gonioscopy (exam of the front part of the eye), and fundoscopy (exam of the back of the eye).
The diagnostic tests discussed above will provide the foundation for assigning a stage and grade to the patient’s malignant melanoma.
- Oral malignancies. For these tumors, staging is fairly straightforward and extremely prognostic. While the World Health Organization’s staging system is considered limited in its application (tumor size is not standardized to the size of the patient and histologic appearance and other histologic-based indices are not considered), it is often still used:
- Stage I: Size of primary tumor is less than or equal to 2 centimeters (cm) in diameter with no involvement of lymph nodes.
- Stage II: Size of primary tumor 2 to 4 cm in diameter with no involvement of lymph nodes.
- Stage III: Size of primary tumor greater than or equal to 4 cm in diameter and/or metastasis to lymph nodes.
- Stage IV: Tumor of any size with distant metastasis present.
Alternative staging systems incorporating histologic criteria have been explored, and while a comprehensive approach has unfortunately yet to be developed, these investigations have continued to find that size and location are extremely relevant.
- Non-oral melanoma. The staging system for non-oral forms of canine melanoma is not well defined and further development with clinical variables and outcome is needed.
There are three histologic features that can be discerned from a biopsy that have been shown to have predictive value. The first, nuclear atypia, is the abnormal appearance of the nucleus of a cell and is considered an indicator of malignancy.
There are several approaches that can be taken to estimate the extent of nuclear atypia, but the assessment is subject to inter-observer variation. It is typically reported as mild, moderate, or severe. Levels greater than or equal to 30% for oral melanomas and greater than or equal to 20% for cutaneous and digit are considered to have poor prognoses.
The second, Ki-67 index, is a quantitative reporting of the cells that are positive for containing the protein Ki-67. This protein increases when cells prepare to divide, and it can be measured with a special staining process. A higher number of positive cells indicates that they are dividing and forming new cells quickly. A Ki-67 proliferative index of greater than or equal to 15% is considered a negative prognostic factor for cutaneous and digital melanomas, as is an index of greater than or equal to 19.5% for oral melanomas.
The mitotic index (MI) is the third and most common feature that can be discerned from a biopsy and is used to estimate the course of the disease. The MI measures the percentage of cells undergoing mitosis (cell division); a higher number of cells that are dividing indicates more aggressive disease. An MI of 3 or higher (out of 10) predicts decreased survival, while an MI of less than 3 predicts a more favorable outlook.
In cutaneous and ocular melanoma cases, the MI is the most reliable element for distinguishing malignant from benign tumors.
A Melanoma Vaccine
For dogs diagnosed with malignant melanoma, local therapy and treatment is necessary and effective at alleviating clinical signs but does not result in long-term disease control (does not prevent metastasis). Merial’s therapeutic vaccine Oncept was developed to address prevention of the spread of existing melanoma; it does not prevent cancer from developing in the first place.
Oncept is a bacterial plasmid DNA vaccine that contains the encoded human melanocyte protein tyrosinase gene. The human form of the protein is used because it is very similar to a dog’s, but the dog’s immune system identifies it as foreign substance, triggering an immune response against the native tyrosinase expressed on the dog’s melanoma cells and targeting them for elimination. The vaccine has been commercially available since 2007. It is used for the adjuvant treatment of Stage II and III oral malignant melanoma after local and regional control with surgery and/or radiation.
Preliminary studies reported that the survival times are significantly longer (increased to 476 days or more) with the use of the vaccine combined with surgery compared to those not treated with the vaccine. Also, fewer than 50% succumbed to metastasis within one year of initial surgery. (There is no survival benefit for dogs with Stage I who receive the vaccine, so routine monitoring alone is recommended after tumor removal in these cases.)
The vaccine is administered every other week for four treatments to mount the initial response; boosters are then administered every six months provided the dog’s staging remains stable. There are no known contraindications for the use of this product in dogs, and the treatment has been found to be safe and well-tolerated. Irritation at the administration site and loss of pigment from heavily pigmented areas (due to the immune system advancing on the dog’s own normal melanocytes) are the most commonly reported side effects.
Oncept does not replace traditional therapies, nor is it considered effective in cases that do not have local control. Use of the vaccine alone (without any other treatments) is extremely unlikely to affect the tumor or even prevent growth. Variable success rates have been reported when the vaccine has been used in an attempt to delay the progression of metastasis in dogs with Stage IV melanoma; it is theorized that there may not be sufficient time in these cases for an immune response to be mounted; it can take 10 weeks or more before the vaccine takes effect.
Sadly, about 15% of dogs receiving the vaccine die within three months of beginning treatment, in all probability due to the aggressive nature of the disease and insufficient time for the vaccine to be effective.
The vaccine is labeled for use in dogs with oral melanoma but is being used “off-label” for dogs with any type of malignant melanoma as it appears that these cases respond similarly.
Use of the vaccine is considered controversial, primarily because none of the clinical studies conducted so far have definitively tested the efficacy of the treatment. Proper randomized clinical trials – the gold standard for proving whether a treatment is effective – have yet to be conducted. The FDA requires such studies prior to approval; however, Oncept was approved by the USDA, which has no such requirement and thus essentially obtained approval with less convincing clinical trial data. Studies conducted since Oncept’s approval have reported contradictory results; only some demonstrated extended survival times.
It is still possible that Oncept is beneficial; in the experience of many veterinary oncologists it is considered effective at delaying metastatic disease when compared to surgery alone and therefore it is incorporated into the treatment plan. Some of the institutions that conducted the studies that found no increase in survival time continue to recommend the vaccine for use.
TYPES OF MELANOMA
In dogs, there are four primary types of melanoma that can occur: oral (anywhere around the mouth or oral cavity); digital/subungal (around the nail bed and in, on, and between toes); cutaneous (skin); and ocular (in and around the eye). Each type has its own clinical presentation and biological behavior.
Oral Melanoma. Melanomas in and around the mouth are considered the most common oral malignancies that occur in dogs. It is estimated that this cancer accounts for anywhere from 14 to 45% of all oral tumors and 80 to 85% of all malignant melanomas.
This form of melanoma typically occurs in dogs ages 10 years and older and in smaller dogs; dogs with heavily pigmented mucous membranes are at higher risk. Tumors can occur anywhere in the oral cavity and surrounding areas, with the majority found in the gingiva/gums. The next most common site is the lips, and then the hard and soft palate. Fewer than 5% develop on the tongue.
Growths tend to be solitary, appearing as a distinct lump or as a flat plaque-like lesion that may or may not be ulcerated. Tumor colors may vary from black to gray to pink or with varied coloring; up to 33% have no pigment at all. Symptoms can include facial swelling; bad breath/mouth odor; abnormal breathing sounds; difficulty chewing, eating, or swallowing; loose teeth; bleeding from the mouth; excessive salivation; and weight loss.
Malignant oral melanomas are quite locally invasive, often infiltrating nearby tissue and bone. At the time of diagnosis, 57% of cases have radiographic evidence of bone involvement. The likelihood for metastasis is high (80 to 85%) with the most common site being the regional lymph nodes, followed by the lungs and other distant organs.
Digital (Toe) / Subungal (Nailbed) Melanoma. This is the second most common type of malignant melanoma diagnosed in dogs, accounting for 15 to 20% of all melanoma cases and 11% of all tumors involving the digits.
Local invasion is a common feature of this form, with many dogs having evidence of bone damage. Anatomically, the forelimbs are slightly more likely (57.1%) than the hindlimbs (42.9%) to develop a melanocytic tumor.
Dogs with black coats tend to have a higher incidence of the disease. It tends to present as a solitary tumor between the toes, on the foot pad, or on the nailbed, causing swelling of the area and sometimes loss of the toenail.
This type of tumor often develops a secondary infection that can initially misdirect the diagnosis. Lameness is often the first noticeable symptom; swelling with bleeding or discharge from the affected area may also occur, and dogs may lick or chew the area.
Like the oral form of the disease, the digital is extremely aggressive with a dismal metastatic rate of 80%.
Cutaneous Melanoma. This is common in dogs and accounts for about 5 to 7% of all canine skin tumors. These tumors can form anywhere on the skin, and while most are malignant in humans, the majority are benign in dogs.
Benign skin melanomas are usually solitary, small, well-defined, deeply pigmented, firm, and move freely over underlying structures. The malignant form varies considerably in appearance, regardless of the location, and is usually asymmetrical. The color is variable, ranging from gray or brown to black, red, or even dark blue; they may have areas of pigmentation intermingled with areas of no pigment.
Malignant cutaneous melanomas are found most frequently on the head, ventral abdomen, and scrotum. The tumors tend to be fast-growing, and are often ulcerated and have developed a secondary infection. They are typically detected at a late stage with metastasis often detectable in regional lymph nodes. Cutaneous melanomas occurring on a mucocutaneous junction (a region of the body where the mucous membranes transitions to skin) have a higher potential to be aggressive and should be considered for treatment as a malignant form.
Ocular Melanoma. Melanoma can occur in and around a dog’s eyes. It can affect the eyelids, conjunctiva (the mucous membrane that covers the front of the eye and lines the inside of the eyelids), orbit (eye socket/eyeball), limbus (border of the cornea and the sclera), and uvea (the middle layer of the eye). Each location may exhibit different biological behaviors.
The good news is that these are frequently benign and rarely metastasize. That said, they can cause discomfort and problems as they grow, including vision impairment and blindness.
Malignancy tends to occur in the melanomas that form on the conjunctiva and in some of those that form on the eyelid and uveal. Additionally, malignant melanoma existing elsewhere in the body has the potential to metastasize to the eye. In general, ocular melanomas are less aggressive than the oral form; within the ocular melanoma group, the uveal form is characterized as being the most aggressive.
Symptoms of ocular melanoma can include a dark-colored mass in the eye or eyelid, darkening of the iris, irritation and redness of the eye, tearing, cloudy eyes, swelling in or around the eye, and twitching of the muscles around the eye.
The first goal of melanoma treatment is to establish local and regional control, which is closely followed by the pursuit of systemic control.
Surgery. This is the primary and most common treatment option for all types of melanoma, including benign tumors. Complete surgical excision of the tumor, surrounding tissue, and any affected bone is required in an effort to obtain clean margins and effective local control. Dogs who have their tumors completely removed with surgery have the lowest chance of experiencing tumor regrowth during their lifetime. Not only can the surgical option occur promptly, it has increased curative intent and tends to be less expensive when compared to other modalities. The extent of the surgery will depend on the anatomic site and size of the melanoma.
Cutaneous melanomas usually require removal by lumpectomy/surgery, while other locations require a more aggressive excision.
Removal of a digital tumor often includes the amputation of the affected toe (with removal of all three phalanges to ensure adequate margins). Surgery to remove melanomas on the larger weight-bearing paw pads can be challenging, as there is the potential for loss of leg function; sometimes amputation of the limb may be the best course of action.
With ocular melanoma, the recommended treatment is enucleation (surgical removal of the eye) when tumors are confined inside the eye.
Oral melanomas may require partial removal of the maxilla or mandible (jaw) bones. While this sounds drastic, dogs tend to do very well after this type of surgery and experience little to no impact on function or quality of life. Cosmetic outcomes tend to be acceptable; if needed, reconstructive surgery can be performed to rebuild these areas.
Other melanoma sites within the oral cavity, such as sublingual or hard palate tumors, are prohibitive for complete surgical removal. Debulking surgeries can, however, reduce the amount of tumor present, but with incomplete surgical removal, oral melanomas tend to regrow quickly (often within days or weeks); subsequently, additional therapy protocols should be considered.
Recently, veterinary specialists have started advocating for removal of the regional lymph nodes and application of radiation therapy to the tumor site if tumor removal is incomplete or the disease has been found to have infiltrated the nodes. It is theorized that this change in protocol might account for the improved survival times occurring in nonvaccinated cases (see “Oncept: A Melanoma Vaccine,” on page 20).
Radiation Therapy. Melanomas were previously considered resistant to radiation therapy (RT), but many more recent studies are finding that there is a significant role for RT in achieving satisfactory local primary tumor control. In particular, RT is an effective treatment for malignant melanomas that cannot be surgically removed due to size or location, or as an adjunct treatment for tumors that either were not, or could not, be completely removed, and/or for cases where the disease has metastasized to local lymph nodes without distant metastasis.
Melanomas tend to respond best to hypofractionated/coarse fraction (radiation given less frequently but in larger doses) RT, typically administered once a week for four weeks and requiring anesthesia. In addition to the tumor site, RT will usually also be administered to the local lymph nodes if metastatic disease has been confirmed.
Side effects from RT tend be uncommon but may include sloughing of nails and foot pad surfaces and mild irritation of the mucous membranes of the mouth. If they do occur, they usually heal within one to two weeks and have minimal impact.
Tumors treated with RT can shrink significantly and may even become undetectable; accordingly, they can remain stable for a period of time. Compared to melanomas treated with surgical removal, however, those treated with RT alone have an increased incidence of recurrence. About 25 to 31% of dogs with oral malignant melanoma that is treated with RT respond partially and 51 to 69% respond completely.
Chemotherapy. Used alone, chemotherapy has not shown to be of much benefit for local control. Because options for treating canine malignant melanoma are fairly limited, chemotherapy has traditionally been used in an attempt to achieve systemic control in combination with surgery and/or radiation therapy.
The drugs typically used in the standard chemotherapy protocols include carboplatin, cisplatin, dacarbazine, melphalan, and doxorubicin.
Unfortunately, there are an increasing number of studies that are demonstrating that chemotherapy as an adjunct treatment does not have a significant impact on either time to progression or overall survival, even when compared to local treatment alone. There is extensive literature on the human counterpart of this approach that suggests melanoma is extremely resistant to chemotherapy. However, chemotherapy has been the most effective treatment available for delaying metastasis until the recent release of the melanoma vaccine (see “A Melanoma Vaccine,” below). At this time, it is still considered a viable but limited treatment option for dogs who don’t respond to the vaccine.
Targeted Chemotherapy. Although not a chemotherapy drug in the traditional sense, Palladia (toceranib) is a novel FDA-approved anticancer drug developed specifically for dogs. While it is labeled for use in dogs diagnosed with mast cell tumors, it has been evaluated for use against other forms of cancer.
Whereas traditional chemotherapy destroys all rapidly dividing cells, Palladia, a tyrosine kinase inhibitor, is a targeted therapy that inhibits specific receptors on the surface of cancer cells and nearby blood vessels (cutting off blood supply) that may result in delaying tumor growth and the progression of the disease. Palladia may be considered in cases that have become unresponsive to vaccine immunotherapy or standard chemotherapy protocols.
Anecdotal reports present varying responses to the drug, ranging from dogs having stable to partial responses for several months to others having no notable response.
On the Horizon: Melanoma Treatments in Development
There are a number of studies involving immunotherapy and other various novel approaches for the treatment of malignant melanoma currently under development.
- The University of Pennsylvania School of Veterinary Medicine has discovered that, when used with surgery, reserpine (an FDA-approved drug used to control blood pressure) hampers metastasis in an animal model. Resperine acts by preventing tumor-derived extracellular vesicles (TEVs) from fusing to healthy cells and spreading malignancy. The study’s findings show that moderate doses of reserpine given to mice with melanoma prior to and following surgery disrupted the uptake of TEVs by healthy cells, reduced the spread of the cancer, and significantly prolonged survival.
- The Veterinary Center for Clinical Trials at the University of California, Davis, has the following melanoma clinical trials underway:
- OMX-4.80 (Zox): Tumors can be resistant to radiation therapy because low levels of oxygen in the tumors can lead to local immune suppression. This study will examine the oxygenated protein drug Zox as part of a treatment protocol to carry oxygen to the tumor and hopefully restore normal oxygen levels and make it more responsive to treatment.
- IL-15: The purpose of this study is to determine the maximum tolerated dose and efficacy of an inhaled immunotherapy protocol against metastatic osteosarcoma or melanoma growing within the lungs.
- The University of Florida College of Veterinary Medicine is currently recruiting dogs recently diagnosed with malignant melanoma for a clinical investigational research trial for the development of a vaccine for the future treatment or prevention of melanoma in dogs. In prior laboratory experiments and clinical trials in healthy dogs, this vaccine has shown to cause the body to produce a response that kills melanoma cells.
- In September 2018, the journal PLOS Genetics published a multi-year study that used multiple genomic analysis techniques to identify several gene mutations that could be the keys to what drives melanoma in dogs. Medical researchers and collaborators with Translational Genomics Research Institute (TGen) looked at 37 canine tumors and 17 control samples using genomic analysis tools. Mutations were identified in a gene called PTPRJ, a tumor suppressor gene. Cancer-activating mutations in the RAS gene were identified in nine of the tumors, as were changes in the genes MDM2 and TP53. This furthers understanding of melanoma biology and serves as a roadmap to developing and evaluating genome-based treatment strategies.
- A study pubished in Molecular Pharmaceutics in April 2018 (“Treatment of Canine Oral Melanoma with Nanotechnology-Based Immunotherapy and Radiation,” Hoopes, et al.) assessed the efficacy and tumor immunopathology of two nanotechnology-based immune adjuvants combined with radiation therapy for the treatment of malignant oral melanoma. Results suggest that the addition of the immune adjuvants (a plant-based virus-like nanoparticle and a magnetic iron oxide nanoparticle) to a hypofractionated radiation regimen increases the immune cell infiltration in the tumor, extends the period of tumor control, and has important systemic therapeutic potential.
- The National Veterinary Cancer Registry is assessing the safety and effectiveness of iniparib, a novel anticancer agent, in combination with one dose of carboplatin, when given to dogs with malignant melanomas, mammary tumors, carcinomas of the head and neck, and soft tissue sarcomas. Iniparib has been safely evaluated in human patients with cancer and in normal, non-tumor-bearing dogs. Carboplatin is a commonly used chemotherapy drug for the treatment of cancer in dogs.
- In collaboration with the University of Wisconsin Carbone Cancer Center, UW Veterinary Care is developing a new approach to treating melanoma that has spread beyond the primary tumor, utilizing immune responses to recognize and destroy cancer (immunotherapy) in combination with low-dose radiation therapy, which may improve the anti-tumor potency of the immunotherapy.
Malignant melanoma is one of the few cancers in dogs for which anatomic location is an extremely important prognostic indicator. Dogs diagnosed with Stage I melanomas have significantly longer survival times than dogs diagnosed with Stage II-IV disease, regardless of treatment chosen.
Negative prognostic factors that affect all types of malignant melanomas include metastasis and size of the tumor.
- Size of primary tumor is prognostic for metastasis and survival time (the smaller the tumor, the better).
- A mitotic index less than or equal to 3 is associated with a better prognosis.
- In general, the closer the tumor is to the front of the mouth, the better the prognosis.
- The median survival time (MST) for untreated dogs is 65 days.
- Survival times following surgery have been estimated at 17 to 18 months for Stage 1; 5 to 6 months for Stage II; 3 months for Stage III, and 1 month for Stage IV.
- Survival time following removal of mandible is 9 to 11 months. In about 22% of the cases, the cancer will recur.
- Survival time following removal of maxilla is about 4.5 to 10 months; about 48% of the cases will recur.
- Response to radiation therapy is about 80%, with survival times of 211 to 363 days.
- The median survival time for dogs without lymph node involvement or metastasis and treated with surgical amputation of the digit is 12 months, with 42 to 57% surviving one year and 11 to 13% surviving two years.
- Digital melanomas not located on the nail bed and having a low mitotic index are often cured with surgery alone.
- Most cutaneous melanomas are benign, in which case the prognosis is excellent.
- About 65% of dogs with cutaneous malignancy succumb within two years due to local recurrence or metastasis.
- Dogs with malignant tumors that are less than 4 cm have a significantly better median survival time (12 months) than tumors greater than or equal to 4 cm (4 months). About 46% of dogs with the malignant tumors that are smaller than 4 cm will survive for at least two years.
- Dogs with well-differentiated malignant tumors and a mitotic index less than or equal to 2 have an MST of 104 weeks.
- Dogs with poorly differentiated malignant tumors and a mitotic index greater than or equal to 3 have an MST of 30 weeks.
- The majority of ocular melanomas are benign, with an excellent prognosis.
- Uveal is the most common malignant form, characterized by aggressive behavior.
- Only 4 to 8% of malignant uveal melanomas metastasize to lungs and liver.
- Malignant tumors removed by enucleation have a low incidence of reoccurrence.
While there are other forms of skin cancer that develop in dogs, melanoma is the most common. If you find any raised lumps or bumps with or without coloration on your dog, consult your veterinarian as soon as possible.
I just did that very thing. My three-year-old mixed breed dog Tico has allergies, requiring frequent baths. I take that time to check him thoroughly – and this time I found a growth on the pad of his paw. We have an appointment next week with a veterinary specialist in internal medicine and oncology. I may be paranoid but after writing this, the fifth article in a series for WDJ on the most common canine cancers, I have earned a little overreaction.
The good news is that canine malignant melanoma is proving to be uniquely responsive to immune-based therapies, and there is evidence that the immune system could modulate the progression and metastasis of the disease. See “On the Horizon: Melanoma Treatments in Development,” on page 22 for more information.